Efavirenz, (4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-1H-3,1-benzoxazin-2-one, is one of the preferred agents used in combination therapy for first-line treatment of human immunodeficiency virus (HIV).

The synthesis of efavirenz and structurally similar reverse transcriptase inhibitors are for example disclosed in WO 95/20389, the asymmetric synthesis of an enantiomeric benzoxazinone by an enantioselective acetylide addition and cyclization sequence is disclosed in Thompson, et al., Tetrahedron Letters 1995, 36, 8937-8940 and WO 96/37457.
WO 98/51676 A to Merck discloses the method for preparation of efavirenz starting from 4-chloro aniline. Due to the nature of the amino group, this method however requires protection and deprotection steps making the overall process cumbersome.
In Jiang, Wang and Yang in Tett. Lett (2001), 42 (24), 4083-4085 a process is disclosed which avoids such protection and deprotection steps by application of a five step procedure starting from nitro-bromo-chlorobenzene. This method requires reactions including the use of sodium iodate and osmium tetroxide, a palladium catalyzed coupling reaction and a nickel catalyzed reduction to obtain trifluoromethyl-(2-amino-5-chloro-phenyl)ketone. Subsequent steps to the final product efavirenz include the ring closure of (S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol using phosgene or derivatives thereof.
The high toxicity and limited availability of at least some the required reagents, however, exclude this process from being applied on industrial scale.
WO2012079235, WO201297510 and WO201297511 to Lonza disclose a short route to efavirenz starting from 1,4-dichlorobenzene. However, cyclization of the intermediate (4S)-4-cyclopropyl-2-(2,5-dichloro-phenyl)-1,1,1-trifluoro-but-3-yn-2-ol is effected by first converting the hydroxy moiety into a carbamate using chlorosulphonylisocyanate and subsequent ring closure applying a copper catalyzed Ullmann-type reaction. The overall yield however were only up to 45% and thus too low to allow commercial application.
Therefore, there was still a need for a short and efficient route to efavirenz using readily available reagents.